This invention relates to newly synthesized platinum complexes. The use of these complexes in anti-tumor chemotherapy is also described.
Cis-platinum (CDDP) is a highly effective drug in the treatment of several neoplastic diseases in humans (Loehrer et al. (1984) Ann. Int. Med. V 100, pp 704-713). However, its use is limited by severe systemic toxicity, particularly nephrotoxicity and neurotoxicity (Zwelling et al. Platinum Complexes. In: Pharmacologic principles of cancer treatment (1982) Ed by B. A. Chabner, Saunders, Philadelphia, Penn.). In an attempt to modify the therapeutic index of CDDP, new derivatives have been synthesized during the last decade. However, the development of some promising analogues has been prevented by their low hydrosolubility, which may decrease their potential for clinical use (Burchenal et al. (1979) Cancer Treat. Rep. V 63, pp 1493-1497).
In U.S. Pat. No. 4,256,652 are described certain platinum compounds comprising resolved stereoisomers of 1,2 diaminocyclohexane (DACH). The isomers utilized were cis-DACH, trans-RR-DACH and trans-SS-DACH. The platinum compounds described therein contained, in addition to a resolved DACH isomer, two hydrophilic platinum ligands such as bromide, iodide, nitrate, bromoacetate, sulfate or glucuronate. The platinum compounds comprising the trans-RR-DACH were described as often more therapeutically effective than those bearing cis-DACH.
In European Patent Application number 184107104.6 (public. no. 0130482, Brown et al., published Jan. 1, 1985) many platinum complexes are described. The platinum complexes described therein comprised DACH and carboxylate ligands including:
N-(2-hydroxyethyl)-iminodiacetato PA0 N-(2-acetamido)-diacetato PA0 N-methyliminodiacetato PA0 trans-1,2-cylclopropanedicarboxylato PA0 trans-1,2cyclobutanedicarboxylato PA0 glycinato PA0 isocitratomonoethylester PA0 D,L-isocitratolactone PA0 ascorbato PA0 D-monosaccharato PA0 D-saccharato-1,4-lactone.
These complexes comprised DACH of an undefined stereochemical structure and, in contrast to the complexes of the present invention, was presumably a racemic mixture of all possible DACH stereoisomers. These complexes are further distinguished from those of the present invention by virtue of their carboxylato ligands, analogous in some cases but different.
Featured advantages of the compounds of the present invention include:
(1) High antitumor activity; PA1 (ii) Lowered potential to produce nephrotoxicity; PA1 (iii) Lack of cross-resistance in in vitro antitumor cell cultures resistant to cisplatin (i.e., L1210/cisplatin); PA1 (iv) High aqueous solubility